Intervertebral disc (IVD) degeneration is a primary or secondary cause of low back pain with associated medical costs ranging from at least $20 to $100 billion annually, yet surgical treatment options do not focus on preventing degeneration or repairing discs. The ultimate clinical goal of this research is to provide early and minimally invasive interventions to slow or reverse progression of degeneration and eventually regenerate IVDs. There is strong evidence of IVD degeneration caused by diagnostic discography yet relatively little is known about how needle injury damages IVDs. Needle injection of therapeutics into the IVD is a very promising technique that is reaching clinical trials for growth factor and anti-inflammatory treatments yet there is surprisingly little basic science knowledge using large animal and human models to inform how such treatments should be optimized. The overall hypothesis is that altered biomechanics, catabolic shifts in biosynthesis, and inflammation are interacting factors that must all be addressed to develop optimal repair strategies for IVD degeneration. Aim 1 will characterize and validate bovine whole IVD organ culture models of early degeneration while providing a more mechanistic understanding of co-morbidity associated with needle injection and inflammation. Aim 2 will determine optimal conditions for therapeutic interventions into bovine injury models focused on anti-inflammatory treatments including transport and uptake, dose optimization, and repair experiments. The development of a human whole IVD explant model is an important technical advance that has been acknowledged by experts to have high relevance to the clinical condition. The optimized treatment methods will therefore be applied in Aim 3 to determine the potential for effective treatment interventions on degenerated human IVDs. Preliminary results demonstrate our extensive experience maintaining whole IVD explants from large animals in culture at least 21 days. Distinct biomechanical and biological alterations were measured in response to needle puncture injuries and the addition of exogenous TNFa. We also have a reliable source of live human IVDs from autopsy that we successfully maintained in culture. Our dependent variable measurements focus on biomechanics, catabolic shifts, inflammation, and pain-related factors. The proposed work will address: How does growth factor efficacy depend on IVD integrity and inflammatory state? Does growth factor injection stimulate anabolic biosynthesis in degenerated human IVDs and for how long? Can biomechanical repair and anti-inflammatory treatments be optimized to enhance repair strategies? Addressing these questions will help inform and improve clinical treatments with a more mechanistic understanding of IVD injuries and treatment strategies in large animal and human IVDs.